Blocking the CD40-CD154 pathway has been shown to effectively prolong renal allograft survival in non-human primates. CFZ533 is a novel, fully human, Fc-silent, anti-CD40 monoclonal antibody being developed for use in transplantation. In non-clinical studies, CFZ533 prolonged allograft survival and inhibited T-dependent antibody response (TDAR). To provide an early assessment of the immunosuppressive activity in humans, an immune challenge sub-study was included in the first-in-human trial in healthy subjects. METHODS: A double-blind, placebo controlled, ascending, single-dose study with IV infusions of 0.03, 0.1, 0.3, 1.0 and 3.0 mg/kg or 3.0 mg/kg CFZ533 subcutaneously was conducted. All subjects were immunized with a single subcutaneous dose of a neo-antigen, Keyhole Limpet Hemocyanin (KLH) with alum adjuvant on days 3 and 85. Blood samples for PK, CD40 receptor occupancy (RO) and anti-KLH IgG and IgM profiling were collected at multiple time points during the study. Anti-KLH antibodies were assessed in a validated human ELISA system with a LOQ of 0.7 (IgG) and 2.1 (IgM) μg/mL. RESULTS: A total of 48 subjects were enrolled. All doses of CFZ533 and KLH were well tolerated. CFZ533 PK concentrations were quantifiable at all dose levels tested. At the highest CFZ533 dose, 3 mg/kg, complete peripheral CD40 RO was maintained for 28 days. Representative time-KLH response curves following a single 3 mg/kg dose of CFZ533 are shown in Figure 1.Over the 28 days of full peripheral CD40 RO, complete suppression of the primary immune response was evident in all CFZ533-treated subjects (Panel A/B). After complete CFZ533 washout, all subjects mounted a robust anti-KLH response following a KLH re-challenge on day 85 (Panel C). CONCLUSION: The favorable safety and tolerability profile of CFZ533 coupled with a predictable concentration-CD40 RO relationship and suppression of a primary T-dependent antibody response supports future clinical trials of CFZ533 in transplantation.

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